Citation: Jiangmin Zhu, Qimei Tan, Shiying Fan, Yalin Li, Ling Zhu, Lihong Hong, Yuxia Wang, Chuzhen Zhang, Chen Chen, Lingyi Kong, Jianguang Luo. PROTAC degraders of FSP1 act as potent GPX4 sensitizers to induce ferroptosis for hepatoma treatment[J]. Chinese Chemical Letters, ;2026, 37(5): 111285. doi: 10.1016/j.cclet.2025.111285 shu

PROTAC degraders of FSP1 act as potent GPX4 sensitizers to induce ferroptosis for hepatoma treatment

Jiangsu Key Laboratory of Bioactive Natural Product Research, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China

cpu_lykong@126.com

luojg@cpu.edu.cn

Received Date: 13 February 2025
Revised Date: 14 April 2025
Accepted Date: 7 May 2025
Available Online: 7 May 2025

Figures(4)

Induction of ferroptosis is a promising strategy for tumor treatment. In light of the fact that the inhibition of ferroptosis suppressor protein 1 (FSP1) can enhance the susceptibility of hepatoma cells to glutathione peroxidase 4 (GPX4) inhibitors, we hypothesized that FSP1 degraders may conspicuously improve the therapeutic efficacy of GPX4 inhibitors against hepatoma. Here, we developed a strategy using an iFSP1 analog (FSP1 inhibitor) and the pomalidomide (E3 ligase ligand) to construct proteolysis targeting chimeras (PROTACs) for degrading FSP1. Among these, C7, the first-in-class PROTAC degrader of FSP1, induced FSP1 degradation with a half-maximal degradation concentration (DC₅₀) value of 0.66 µmol/L. The synergistic application of C7 (1 µmol/L) and the GPX4 inhibitor ML162 (100 nmol/L) markedly induced ferroptosis and effectively inhibited hepatoma cells viability. Further mechanism studies revealed that C7 targets FSP1 and down-regulates it through the ubiquitin-proteasome pathway. In vivo experiments demonstrated that the therapeutic alliance of C7 and ML162 markedly surpassed the efficacy of iFSP1 (FSP1 inhibitor) and ML162 in suppressing tumor proliferation. Collectively, these findings indicated that PROTAC degraders of FSP1 function as potent sensitizers of GPX4 inhibitors to induce ferroptosis, thus representing a promising strategy for hepatoma treatment.
- FSP1,
- GPX4,
- PROTACs,
- Degraders,
- Hepatoma
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